Non-Alcoholic Fatty Liver Disease (NAFLD) is defined histologically as a spectrum of liver diseases, ranging from steatosis to steatohepatitis (NASH), and cirrhosis. There is tremendous inter-individual variability in the tendency to develop cirrhosis, the stage of NAFLD that is associated with the greatest liver-related morbidity and mortality. The variable progression of NAFLD may be explained by the "multiple hit hypothesis". According to this hypothesis, a primary insult (i.e., "hit") causes normal livers to accumulate fat. Evidence suggests that the first "hit" that causes fat to accumulate in the liver is insulin resistance, which may be either primary or secondary to obesity. Fatty livers are unusually vulnerable to damage from various secondary insults and NASH develops when fatty livers experience a second "hit", such as exposure to intestinal bacterial products that induce inflammatory cytokines, which cause oxidative stress and further mitochondrial dysfunction. Because NASH does not always culminate in cirrhosis, it is likely that additional "hits" may be required for hepatic fibrosis to occur. Progression from clinically-compensated to decompensated cirrhosis may require further insults. If this "multiple-hit hypothesis" explains the histological and clinical progression of NAFLD, then interventions which remove the vulnerability state by reversing hepatic steatosis, or which prevent the superimposition of the secondary "hits" should be effective treatments. To test the validity of these therapeutic strategies, we propose 3 SPECIFIC AIMS. Aim #1 is to create and maintain a NAFLD registry. This will be accomplished by screening various populations that have a high risk of NAFLD to determine if there are host or environmental factors (i.e., "hits") that distinguish subjects without fatty liver from those with fatty livers, as well as factors that distinguish among the various histologic stages of NAFLD. Aim #2 is to identify promising treatments that may prevent the progression of NAFLD by improving one or more of the "hits". This will be accomplished y retrospective analysis of trials that have already tried to improve the putative, primary "hit" (Aim #2a) and by a prospective valuation of the importance of intestinal bacterial overgrowth, which may generate putative secondary "hits"(Aim #2b). Aim #3 is to design and conduct a Network-wide randomized, controlled trial in patients with NAFLD. Assuming that insulin resistance emerges as a promising target for therapy, we will test the hypothesis that a 12-month course of metformin therapy will produce significant improvement in hepatic steatosis and in NAFLD-related metabolic factors without adverse effects. Completion of these Aims will provide important information about host and environmental factors that promote NAFLD and is likely to identify treatments that prevent the progression from steatosis to NASH and more advanced stages of liver damage.